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We have previously shown that the multidrug resistance protein (MRP) mediates the ATP-dependent membrane transport of the endogenous glutathione conjugate leukotriene C4 (LTC4) and of structurally related anionic conjugates of lipophilic compounds Jedlitschky, Leier, Buchholz, Center and Keppler (1994) Cancer Res. 54, 4833-4836; Leier, Jedlitschky, Buchholz, Cole, Deeley and Keppler (1994) J. Biol. Chem. 269, 27807-27810. We demonstrate in the present study that MRP also mediates the ATP-dependent transport of GSSG, as shown in membrane vesicles from human leukaemia cells overexpressing MRP (HL60/ADR cells) or HeLa cells transfected with an MRP expression vector (HeLa T5 cells) in comparison with the respective parental or control cells. The Km value for ATP-dependent transport of GSSG was 93 +/- 26 microM (mean value +/- S. D. , n=5) in membrane vesicles from HeLa T5 cells. GSH, at a concentration of 100 microM, was not a substrate for any significant ATP-dependent MRP-mediated transport. The transport of GSSG was competitively inhibited by LTC4, by the leukotriene D4 receptor antagonist 3- (3- (2-[7-chloro-2-quinolinylethenyl) phenyl- (3-dimethylamino-3- oxopropyl) -thio-methyl]thio) propanoic acid (MK 571) and by S-decylglutathione, with K1 values of 0. 3, 0. 6 and 0. 7 microM respectively. These studies identify MRP as the membrane glycoprotein which mediates the ATP-dependent export of GSSG from these cells.
Leier et al. (Fri,) studied this question.